Abstract: FR-PO725
Secreted Frizzled Related Protein 2: A New Therapeutic Target for Glomerular Disease?
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1304 Glomerular Diseases: Podocyte Biology
Authors
- Papakrivopoulou, Eugenia, Developmental Biology Unit, UCL Institute of Child Health, London, United Kingdom
- Lindenmeyer, Maja, Nephrological Center, Medical Clinic and Policlinic IV, University of Munich, Munich, Germany
- Mason, William John, Developmental Biology Unit, UCL Institute of Child Health, London, United Kingdom
- Long, David A., Developmental Biology Unit, UCL Institute of Child Health, London, United Kingdom
Background
Wnt/b-catenin signalling,critical during development but silenced in adult kidneys,is re-activated in podocytes following injury and plays a detrimental role in glomerular injury.Secreted frizzled-related proteins (sFRPs) modulate Wnt signalling and are involved in conditions such as myocardial infarction and cancer but their role in glomerular pathology is unknown.Here,we examined the role of sFRP2 in podocyte injury using in vivo and in vitro approaches.
Methods
Glomeruli from patients with minimal change disease,focal and segmental glomerulosclerosis,Type 2 Diabetes Mellitus and healthy donor kidneys were isolated from biopsy specimens and gene expression examined on Affymetrix gene chip arrays. Adriamycin (ADR) nephropathy was induced in Balb/c mice with 10mg/kg IV ADR.sFRP2 neutralising antibody or IgG was injected at day 0, and every 3 days, until day 14.Urine and serum samples were collected at 7 and 14 days.In a separate experiment, mRNA changes were examined in isolated glomeruli 2 days after ADR. An immortalised mouse podocyte cell line was used for in vitro experiments.
Results
sFRP2 mRNA levels were significantly upregulated (6 to 24-fold) versus live donor controls,in all patient cohorts. In mice,ADR injury increased glomerular sFRP2 mRNA expression (2-fold, p<0.05) 48hrs after induction,prior to the appearance of albuminuria and in vitro,ADR induced podocyte sFRP2 mRNA expression (10-fold, p<0.01).Increased sFRP2 staining was observed in podocytes following ADR injury.Exposure of podocytes in vitro to sFRP2 led to longer processes (53± 4.6 vs 76 ± 9.1,arbitrary units,p<0.05) and more processes/cell (8 ± 0.96 vs 11 ± 1.01,p<0.05).Next, we examined the effect of sFRP2 blockade on ADR-induced glomerular injury.ADR significantly increased albuminuria compared to baseline (383.23 vs 0.04mg/24hr, p<0.001,n=10 mice/group) and blood urea nitrogen (BUN) levels (38.14 vs 21.57mg/dL, p<0.05,n=10) at 14 days.sFRP2 inhibition significantly attenuated both albuminuria (40 vs 383 mg/24hr,p<0.05,n= 10) and BUN levels (21.72 vs 38.14mg/dL,n=10,p<0.05) compared to IgG control, at the same time point.No changes in body to kidney weight ratio were observed.
Conclusion
Glomerular sFRP2 expression is upregulated in response to injury.This appears to be detrimental for podocytes as inhibition by antibody blockade attenuates the response to injury.
Funding
- Government Support – Non-U.S.